The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
However, many drugs are not suitable for passive transdermal drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body through intact skin. The method of the invention relates to such an administration technique, i.e., to "electrotransport" or "iontophoretic" drug delivery.
Herein the terms "electrotransport", "iontophoresis", and "iontophoretic" are used to refer to the transdermal delivery of pharmaceutically active agents by means of an applied electromotive force to an agent-containing reservoir. The agent may be delivered by electromigration, electroporation, electroosmosis or any combination thereof. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically induced osmosis. In general, electroosmosis of a species into a tissue results from the migration of solvent in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, i.e., solvent flow induced by electromigration of other ionic species. During the electrotransport process, certain modifications or alterations of the skin may occur such as the formation of transiently existing pores in the skin, also referred to as "electroporation". Any electrically assisted transport of species enhanced by modifications or alterations to the body surface (e.g., formation of pores in the skin) are also included in the term "alectrotransport" as used herein. Thus, as used herein, the terms "electrotransport", "iontophoresis" and "iontophoretic" refer to (1) the delivery ot charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged or uncharged drugs by electroporation, (4) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or ageints by the combined processes of electromigration and electroosmosis.
In present electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the drug is delivered into the body. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery, and usually to circuitry capable of controlling current passing through the device. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode, completing the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Existing electrotransport devices additionally require a reservoir or source of the pharmaceutically active agent which is to be delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired species or agents.
Thus, an electrotransport device or system, with its donor and counter electrodes, may be thought of as an electrochemical cell having two electrodes, each electrode having an associated half cell reaction, between which electrical current flows. Electrical current flowing through the conductive (e.g., metal) portions of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid-containing portions of the device (i.e., the drug reservoir in the donor electrode, the electrolyte reservoir in the counter electrode, and the patient's body) is carried by ions (ionic conduction). Current is transferred from the metal portions to the liquid phase by means of oxidation and reduction charge transfer reactions which typically occur at the interface between the metal portion (e.g., a metal electrode) and the liquid phase (e.g., the drug solution). A detailed description of the electrochemical oxidation and reduction charge transfer reactions of the type involved in electrically assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard and L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980).
The present invention is directed to a method for using such electrotransport drug delivery system so that sensitization of the skin or mucosal tissue is reduced or eliminated during drug administration. Sensitization is a two-phase process involving biological mechanisms totally distinct from those observed in skin irritation. The first phase in sensitization reactions is the induction phase where the skin is initially exposed to a sensitizing agent, such as a drug or other antigen. During this phase, generally no skin reaction occurs. In the induction phase, the sensitizing drug or antigen is presented to T-lymphocytes by the Langerhans cells of the epidermis, either in situ or in the draining lymph node. As a consequence, cells which recognize the antigen, proliferate and differentiate.
The second, subsequent phase, following the establishment of contact allergy, is elicitation where a subsequent re-exposure (i.e., contact with the skin) to the sensitizing drug or antigen results in a manifested skin reaction. This condition is known as allergic contact dermatitis. During elicitation, the antigen is once again presented mainly on Langerhans cells. The T-cells which have differentiated or clonally expanded upon prior exposure now migrate to the treated site and initiate a cascade of skin reaction events which result in local inflammation.
Contact sensitization is a completely different process than irritation. Irritation is caused by and therefore relieved by a different mechanism than that of sensitization. Irritation depends upon a variety of factors including, but not limited to, change in pH and bacterial overgrowth. Ultimaitely, irritation is the result of damage to the cells by cellular response to a toxic agent, i.e., one that irritates. Sensitization, on the other hand, is the result of an allergic cellular response to an agent which is not necessarily intrinsically toxic.
Immune tolerance is a different phenomenon from both sensitization and irritation. Immune tolerance is the state of prolonged unresponsiveness to a specific antigen. Tolerance to contact sensitization has been induced in adult animals by pretreatment of the skin site to which the sensitizing drug or antigen is applied with compounds that act to suppress the animal's immune system (see Rheins et al. (1986) J. Immunol. 136:867-876). Immune tolerance to contact sensitizers was induced in mice by application of arachidonic acid to the local site for several days prior to antigen application (Rheins et al., supra).
A number of countersensitizing agents have been proposed for reducing sensitization and/or irritation reactions associated with transdermal drug delivery. Countersensitizing and/or counter irritating agents which have been used in transdermal drug delivery include metabolic modulators which inhibit drug metabolism by skin enzymes (see U.S. Pat. Nos. 4,885,154 and 5,304,379 to Cormier et al.), corticosteroids such as hydrocoitisone (see U.S. Pat. Nos. 5,049,387 and 5,118,509 to Amkraut and U.S. Pat. Nos. 5,000,956, 5,077,054 and 5,171,576 to Amkraut et al.), antigen processing inhibiting agents such as ammonium chloride (see U.S. Pat. Nos. 5,120,545 and 5,149,539 to Ledger et al.), lysosomal uptake inhibiting agents such as monensin (see U.S. Pat. Nos. 5,130,139 and 5,160,741 to Cormier et al.) and calcium channel blocking agents such as verapamil (see U.S. Pat. No. 5,202,130 to Grant et al.). In addition, the use of corticosteroids such as hydrocortisone (see Int'l Pub. No. WO 95/26782, inventors Cormier et al.) and the buffering of reservoir pH at select ranges (see Int'l Pub. No. WO 95/06497, inventors Cormier et al.) have been proposed to lessen or eliminate skin irritation and/or sensitization associated with electrically assisted transdermal drug delivery.
Cis-urocanic acid has been proposed to be useful for inhibiting or preventing sensitizing effects encountered with passive transdermal delivery of certain drugs. See, e.g., European Patent Publication No. (312,525, published Aug. 31, 1994, and Wille et al., "Topical Delivery of Mast Cell Degranulating Agents for Treatment of Transdermal Drug-Induced Hypersensitivity," Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22:119-120 (1995). In addition, it has been reported by Shimizu et al. in J. Inv. Dermatol., pp. 749-753 (1993), that cis-urocanic acid could induce skin tolerance to a sensitizing drug.
The use of cis-urocanic acid or an analog thereof in reducing or preventing sensitization occurring in conjunction with electrotransport drug delivery is, however, novel and completely unsuggested by the art. An important advantage of using cis-urocanic acid or a cis-urocanic acid analog as a countersensitizing agent is that such compounds are naturally occurring compounds found in skin and body tissue (or metabolites of naturally occurring compounds) and thus use in conjunction with electrotransport drug delivery does not represent the introduction of foreign mater al. Another important advantage is the effectiveness of cis-urocanic acid or an analog thereof in reducing or preventing skin sensitization during electrotransport drug delivery.